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Localizations of Na+-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart

  • Ion channels, receptors and transporters
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Abstract

Novel affinity-purified antibodies against human SGLT1 (hSGLT1) and SGLT2 (hSGLT2) were used to localize hSGLT2 in human kidney and hSGLT1 in human kidney, small intestine, liver, lung, and heart. The renal locations of both transporters largely resembled those in rats and mice; hSGLT2 and SGLT1 were localized to the brush border membrane (BBM) of proximal tubule S1/S2 and S3 segments, respectively. Different to rodents, the renal expression of hSGLT1 was absent in thick ascending limb of Henle (TALH) and macula densa, and the expression of both hSGLTs was sex-independent. In small intestinal enterocytes, hSGLT1 was localized to the BBM and subapical vesicles. Performing double labeling with glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP), hSGLT1 was localized to GLP-1-secreting L cells and GIP-secreting K cells as has been shown in mice. In liver, hSGLT1 was localized to biliary duct cells as has been shown in rats. In lung, hSGLT1 was localized to alveolar epithelial type 2 cells and to bronchiolar Clara cells. Expression of hSGLT1 in Clara cells was verified by double labeling with the Clara cell secretory protein CC10. Double labeling of human heart with aquaporin 1 immunolocalized the hSGLT1 protein in heart capillaries rather than in previously assumed myocyte sarcolemma. The newly identified locations of hSGLT1 implicate several extra renal functions of this transporter, such as fluid absorption in the lung, energy supply to Clara cells, regulation of enteroendocrine cells secretion, and release of glucose from heart capillaries. These functions may be blocked by reversible SGLT1 inhibitors which are under development.

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References

  1. Abdul-Ghani MA, DeFronzo RA, Norton L (2013) Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50 % of filtered glucose load in humans. Diabetes 62:3324–3328

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Balen D, Ljubojevic M, Breljak D, Brzica H, Zlender V, Koepsell H, Sabolic I (2008) Revised immunolocalization of the Na+-D-glucose cotransporter SGLT1 in rat organs with an improved antibody. Am J Physiol Cell Physiol 295:C475–C489

    Article  CAS  PubMed  Google Scholar 

  3. Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F (2009) SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc Res 84:111–118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Basset G, Crone C, Saumon G (1987) Fluid absorption by rat lung in situ: pathways for sodium entry in the luminal membrane of alveolar epithelium. J Physiol 384:325–345

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Basset G, Saumon G, Bouchonnet F, Crone C (1988) Apical sodium-sugar transport in pulmonary epithelium in situ. Biochim Biophys Acta 942:11–18

    Article  CAS  PubMed  Google Scholar 

  6. Bodega F, Sironi C, Armilli M, Porta C, Agostoni E (2010) Evidence for Na+-glucose cotransporter in type I alveolar epithelium. Histochem Cell Biol 134:129–136

    Article  CAS  PubMed  Google Scholar 

  7. Bradford MM (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  8. Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, Feder JN (2010) Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther 1:57–92

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Crafer SM, Pryor JS, Dawson AP (1994) Effect of arterial-portal glucose gradients and phloridzin on bile glucose levels in perfused rat liver. J Physiol 479(Pt 2):281–289

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Dahlin A, Royall J, Hohmann JG, Wang J (2009) Expression profiling of the solute carrier gene family in the mouse brain. J Pharmacol Exp Ther 329:558–570

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Devaskar SU, deMello DE (1996) Cell-specific localization of glucose transporter proteins in mammalian lung. J Clin Endocrinol Metab 81:4373–4378

    CAS  PubMed  Google Scholar 

  12. Diez-Sampedro A, Hirayama BA, Osswald C, Gorboulev V, Baumgarten K, Volk C, Wright EM, Koepsell H (2003) A glucose sensor hiding in a family of transporters. Proc Natl Acad Sci U S A 100:11753–11758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Elfeber K, Köhler A, Lutzenburg M, Osswald C, Galla HJ, Witte OW, Koepsell H (2004) Localization of the Na(+)-D-glucose cotransporter SGLT1 in the blood-brain barrier. Histochem Cell Biol 121:201–207

    Article  CAS  PubMed  Google Scholar 

  14. Elfeber K, Stümpel F, Gorboulev V, Mattig S, Deussen A, Kaissling B, Koepsell H (2004) Na+-D-glucose cotransporter in muscle capillaries increases glucose permeability. Biochem Biophys Res Commun 314:301–305

    Article  CAS  PubMed  Google Scholar 

  15. Evans CM, Williams OW, Tuvim MJ, Nigam R, Mixides GP, Blackburn MR, DeMayo FJ, Burns AR, Smith C, Reynolds SD, Stripp BR, Dickey BF (2004) Mucin is produced by clara cells in the proximal airways of antigen-challenged mice. Am J Respir Cell Mol Biol 31:382–394

    Article  CAS  PubMed  Google Scholar 

  16. Gorboulev V, Schürmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl-Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, Sabolic I, Sendtner M, Koepsell H (2012) Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61:187–196

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Guzelian P, Boyer JL (1974) Glucose reabsorption from bile. Evidence for a biliohepatic circulation. J Clin Invest 53:526–535

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Haase W, Heitmann K, Friese W, Ollig D, Koepsell H (1990) Characterization and histochemical localization of the rat intestinal Na+-D-glucose cotransporter by monoclonal antibodies. Eur J Cell Biol 52:297–309

    CAS  PubMed  Google Scholar 

  19. Haase W, Koepsell H (1989) Electron microscopic immunohistochemical localization of components of Na+-cotransporters along the rat nephron. Eur J Cell Biol 48:360–374

    CAS  PubMed  Google Scholar 

  20. Johnston CJ, Mango GW, Finkelstein JN, Stripp BR (1997) Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. Am J Respir Cell Mol Biol 17:147–155

    Article  CAS  PubMed  Google Scholar 

  21. Joris L, Quinton PM (1989) Evidence for electrogenic Na-glucose cotransport in tracheal epithelium. Pflugers Arch 415:118–120

    Article  CAS  PubMed  Google Scholar 

  22. Kanai Y, Lee W-S, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93:397–404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Kemp PJ, Boyd CAR (1992) Pathways for glucose transport in type II pneumocytes freshly isolated from adult guinea pig lung. Am J Physiol Lung Cell Mol Physiol 263:L612–L616

    CAS  Google Scholar 

  24. Kipp H, Khoursandi S, Scharlau D, Kinne RKH (2003) More than apical: distribution of SGLT1 in Caco-2 cells. Am J Physiol Cell Physiol 285:C737–C749

    Article  CAS  PubMed  Google Scholar 

  25. Lazaridis KN, Pham L, Vroman B, de Groen PC, LaRusso NF (1997) Kinetic and molecular identification of sodium-dependent glucose transporter in normal rat cholangiocytes. Am J Physiol Gastrointest Liver Physiol 272:G1168–G1174

    CAS  Google Scholar 

  26. Lee W-S, Kanai Y, Wells RG, Hediger MA (1994) The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. J Biol Chem 269:12032–12039

    CAS  PubMed  Google Scholar 

  27. Liakos A, Karagianis T, Athanasiadou E, Satigianni M, Mainou M, Paptheodorou K, Bekiari E, Tsapas A (2014) Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 16:984–993

    Article  CAS  PubMed  Google Scholar 

  28. Liu JJ, Lee T, DeFronzo RA (2012) Why do SGLT2 inhibitors inhibit only 30–50 % of renal glucose reabsorption in humans? Diabetes 61:2199–2204

    Article  CAS  PubMed  Google Scholar 

  29. Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC (2014) Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab 16:215–222

    Article  CAS  PubMed  Google Scholar 

  30. Mamchaoui K, Makhloufi Y, Saumon G (2002) Glucose transporter gene expression in freshly isolated and cultured rat pneumocytes. Acta Physiol Scand 175:19–24

    Article  CAS  PubMed  Google Scholar 

  31. Masyuk AI, Masyuk TV, Tietz PS, Splinter PL, LaRusso NF (2002) Intrahepatic bile ducts transport water in response to absorbed glucose. Am J Physiol Cell Physiol 283:C785–C791

    Article  CAS  PubMed  Google Scholar 

  32. Neumiller JJ (2014) Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Drugs Context 3:212262, ISSN 1740-4398

    PubMed Central  PubMed  Google Scholar 

  33. Parker HE, Adriaenssens A, Rogers G, Richards P, Koepsell H, Reimann F, Gribble FM (2012) Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion. Diabetologia 55:2445–2455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Parker HE, Habib AM, Rogers GJ, Gribble FM, Reimann F (2009) Nutrient-dependent secretion of glucose-dependent insulinotropic polypeptide from primary murine K cells. Diabetologia 52:289–298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Pezzulo AA, Gutierrez J, Duschner KS, McConnell KS, Taft PJ, Ernst SE, Yahr TL, Rahmouni K, Klesney-Tait J, Stoltz DA, Zabner J (2011) Glucose depletion in the airway surface liquid is essential for sterility of the airways. PLoS ONE 6:e16166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Poppe R, Karbach U, Gambaryan S, Wiesinger H, Lutzenburg M, Kraemer M, Witte OW, Koepsell H (1997) Expression of the Na+-D-glucose cotransporter SGLT1 in neurons. J Neurochem 69:84–94

    Article  CAS  PubMed  Google Scholar 

  37. Powell DR, Smith M, Greer J, Harris A, Zhao S, DaCosta C, Mseeh F, Shadoan MK, Sands A, Zambrowicz B, Ding ZM (2013) LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther 345:250–259

    Article  CAS  PubMed  Google Scholar 

  38. Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM (2008) Glucose sensing in L cells: a primary cell study. Cell Metab 8:532–539

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Reynolds SD, Malkinson AM (2010) Clara cell: progenitor for the bronchiolar epithelium. Int J Biochem Cell Biol 42:1–4

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Rutkovskiy A, Bliksoen M, Hillestad V, Amin M, Czibik G, Valen G, Vaage J, Amiry-Moghaddam M, Stenslokken KO (2013) Aquaporin-1 in cardiac endothelial cells is downregulated in ischemia, hypoxia and cardioplegia. J Mol Cell Cardiol 56:22–33

    Article  CAS  PubMed  Google Scholar 

  41. Rutkovskiy A, Valen G, Vaage J (2013) Cardiac aquaporins. Basic Res Cardiol 108:393

    Article  PubMed  Google Scholar 

  42. Sabolic I, Skarica M, Gorboulev V, Ljubojevic M, Balen D, Herak-Kramberger CM, Koepsell H (2006) Rat renal glucose transporter SGLT1 exhibits zonal distribution and androgen-dependent gender differences. Am J Physiol Ren Physiol 290:F913–F926

    Article  CAS  Google Scholar 

  43. Sabolic I, Valenti G, Verbavatz J-M, Van Hoek AN, Verkman AS, Ausiello DA, Brown D (1992) Localization of the CHIP28 water channel in rat kidney. Am J Physiol 263(Cell Physiol 32):C1225–C1233

    CAS  PubMed  Google Scholar 

  44. Sabolic I, Vrhovac I, Eror DB, Gerasimova M, Rose M, Breljak D, Ljubojevic M, Brzica H, Sebastiani A, Thal SC, Sauvant C, Kipp H, Vallon V, Koepsell H (2012) Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am J Physiol Cell Physiol 302:C1174–C1188

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Shibazaki T, Tomae M, Ishikawa-Takemura Y, Fushimi N, Itoh F, Yamada M, Isaji M (2012) KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent Models. J Pharmacol Exp Ther 342:288–296

    Article  CAS  PubMed  Google Scholar 

  46. Singh G, Katyal SL (1997) Clara cells and Clara cell 10 kD protein (CC10). Am J Respir Cell Mol Biol 17:141–143

    Article  CAS  PubMed  Google Scholar 

  47. Stripp BR, Reynolds SD (2008) Maintenance and repair of the bronchiolar epithelium. Proc Am Thorac Soc 5:328–333

    Article  PubMed Central  PubMed  Google Scholar 

  48. Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H (1992) Immunohistochemical localization of Na+-dependent glucose transporter in rat jejunum. Cell Tissue Res 267:3–9

    Article  CAS  PubMed  Google Scholar 

  49. Thenappan T, Goel A, Marsboom G, Fang YH, Toth PT, Zhang HJ, Kajimoto H, Hong Z, Paul J, Wietholt C, Pogoriler J, Piao L, Rehman J, Archer SL (2011) A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med 183:1080–1091

    Article  PubMed Central  PubMed  Google Scholar 

  50. Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P (2012) Acute and chronic effects of SGLT2 blockage on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302:R75–R83

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Uldry M, Thorens B (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch-Eur J Physiol 447(5):480–489

    Article  CAS  Google Scholar 

  52. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, Koepsell H, Thomson SC, Rieg T (2014) SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Ren Physiol 306:F194–F204

    Article  CAS  Google Scholar 

  53. Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T (2010) SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol 22:104–112

    Article  PubMed  Google Scholar 

  54. Veyhl M, Keller T, Gorboulev V, Vernaleken A, Koepsell H (2006) RS1(RSC1A1) regulates the exocytotic pathway of Na+-D-glucose cotransporter SGLT1. Am J Physiol Ren Physiol 291:F1213–F1223

    Article  CAS  Google Scholar 

  55. von Lewinski D, Rainer PP, Gasser R, Huber M-S, Khafaga M, Wilhelm B, Haas T, Mächler H, Rössl U, Pieske B (2010) Glucose-transporter-mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients. Metabolism 59:1020–1028

    Article  Google Scholar 

  56. Wright EM, Loo DDF, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794

    Article  CAS  PubMed  Google Scholar 

  57. Yu AS, Hirayama BA, Timbol G, Liu J, Diez-Sampedro A, Kepe V, Satyamurthy N, Huang SC, Wright EM, Barrio JR (2013) Regional distribution of SGLT activity in rat brain in vivo. Am J Physiol Cell Physiol 304:C240–C247

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, Ruff D, Shadoan M, Banks P, Mseeh F, Rawlins DB, Goodwin NC, Mabon R, Harrison BA, Wilson A, Sands A, Powell DR (2012) LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther 92:158–169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Zhou L, Cryan EV, D’Andrea MR, Belkowski S, Conway BR, Demarest KT (2003) Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J Cell Biochem 90:339–346

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors acknowledge the technical help by Mrs. Eva Heršak. This work was supported by the grant 022-0222148-2146 from Croatian Ministry for Science, Education and Sports (I.S.) and by Deutsche Forschungsgemeinschaft Grant KO 872/5-1 (H.K.).

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Authors and Affiliations

  1. Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000, Zagreb, Croatia

    Ivana Vrhovac, Daniela Balen Eror, Davorka Breljak & Ivan Sabolić

  2. Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany

    Dirk Klessen

  3. Merck KgaA, Darmstadt, Germany

    Christa Burger

  4. Clinical Hospital Sisters of Mercy, Zagreb, Croatia

    Ognjen Kraus

  5. Clinical Hospital Dubrava, Zagreb, Croatia

    Nikola Radović

  6. Clinical Hospital Merkur, Zagreb, Croatia

    Stipe Jadrijević

  7. Department of Thoracic and Cardiovascular Surgery, University Hospital of Würzburg, Würzburg, Germany

    Ivan Aleksic & Thorsten Walles

  8. Department of Anesthesiology and Critical Care Medicine, University Hospital Halle, Halle, Saale, Germany

    Christoph Sauvant

  9. Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstr. 6, 97070, Würzburg, Germany

    Hermann Koepsell

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  1. Ivana Vrhovac
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Correspondence to Ivan Sabolić or Hermann Koepsell.

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Ivan Sabolić and Hermann Koepsell, both senior authors, contributed to this study with equal intellectual and organizational input.

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Vrhovac, I., Balen Eror, D., Klessen, D. et al. Localizations of Na+-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch - Eur J Physiol 467, 1881–1898 (2015). https://doi.org/10.1007/s00424-014-1619-7

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